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Journal articles on the topic 'Virtual ribosome'

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Author: Grafiati
Published: 6 September 2023

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1

Caulfield, Thomas R., Karen E. Hayes, Yushi Qiu, Mathew Coban, Joon Seok Oh, Amy L. Lane, Takehiko Yoshimitsu, Lori Hazlehurst, John A. Copland, and Han W. Tun. "A Virtual Screening Platform Identifies Chloroethylagelastatin A as a Potential Ribosomal Inhibitor." Biomolecules 10, no. 10 (October 5, 2020): 1407. http://dx.doi.org/10.3390/biom10101407.

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Chloroethylagelastatin A (CEAA) is an analogue of agelastatin A (AA), a natural alkaloid derived from a marine sponge. It is under development for therapeutic use against brain tumors as it has excellent central nervous system (CNS) penetration and pre-clinical therapeutic activity against brain tumors. Recently, AA was shown to inhibit protein synthesis by binding to the ribosomal A-site. In this study, we developed a novel virtual screening platform to perform a comprehensive screening of various AA analogues showing that AA analogues with proven therapeutic activity including CEAA have significant ribosomal binding capacity whereas therapeutically inactive analogues show poor ribosomal binding and revealing structural fingerprint features essential for drug-ribosome interactions. In particular, CEAA was found to have greater ribosomal binding capacity than AA. Biological tests showed that CEAA binds the ribosome and contributes to protein synthesis inhibition. Our findings suggest that CEAA may possess ribosomal inhibitor activity and that our virtual screening platform may be a useful tool in discovery and development of novel ribosomal inhibitors.
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2

Buckley, McKenna E., Audrey R. N. Ndukwe, Pramod C. Nair, Santu Rana, Kathryn E. Fairfull-Smith, and Neha S. Gandhi. "Comparative Assessment of Docking Programs for Docking and Virtual Screening of Ribosomal Oxazolidinone Antibacterial Agents." Antibiotics 12, no. 3 (February 24, 2023): 463. http://dx.doi.org/10.3390/antibiotics12030463.

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Oxazolidinones are a broad-spectrum class of synthetic antibiotics that bind to the 50S ribosomal subunit of Gram-positive and Gram-negative bacteria. Many crystal structures of the ribosomes with oxazolidinone ligands have been reported in the literature, facilitating structure-based design using methods such as molecular docking. It would be of great interest to know in advance how well docking methods can reproduce the correct ligand binding modes and rank these correctly. We examined the performance of five molecular docking programs (AutoDock 4, AutoDock Vina, DOCK 6, rDock, and RLDock) for their ability to model ribosomal–ligand interactions with oxazolidinones. Eleven ribosomal crystal structures with oxazolidinones as the ligands were docked. The accuracy was evaluated by calculating the docked complexes’ root-mean-square deviation (RMSD) and the program’s internal scoring function. The rankings for each program based on the median RMSD between the native and predicted were DOCK 6 > AD4 > Vina > RDOCK >> RLDOCK. Results demonstrate that the top-performing program, DOCK 6, could accurately replicate the ligand binding in only four of the eleven ribosomes due to the poor electron density of said ribosomal structures. In this study, we have further benchmarked the performance of the DOCK 6 docking algorithm and scoring in improving virtual screening (VS) enrichment using the dataset of 285 oxazolidinone derivatives against oxazolidinone binding sites in the S. aureus ribosome. However, there was no clear trend between the structure and activity of the oxazolidinones in VS. Overall, the docking performance indicates that the RNA pocket’s high flexibility does not allow for accurate docking prediction, highlighting the need to validate VS. protocols for ligand-RNA before future use. Later, we developed a re-scoring method incorporating absolute docking scores and molecular descriptors, and the results indicate that the descriptors greatly improve the correlation of docking scores and pMIC values. Morgan fingerprint analysis was also used, suggesting that DOCK 6 underpredicted molecules with tail modifications with acetamide, n-methylacetamide, or n-ethylacetamide and over-predicted molecule derivatives with methylamino bits. Alternatively, a ligand-based approach similar to a field template was taken, indicating that each derivative’s tail groups have strong positive and negative electrostatic potential contributing to microbial activity. These results indicate that one should perform VS. campaigns of ribosomal antibiotics with care and that more comprehensive strategies, including molecular dynamics simulations and relative free energy calculations, might be necessary in conjunction with VS. and docking.
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3

Jensen, Travis L., William F. Hooper, Sami R. Cherikh, and Johannes B. Goll. "RP-REP Ribosomal Profiling Reports: an open-source cloud-enabled framework for reproducible ribosomal profiling data processing, analysis, and result reporting." F1000Research 10 (February 24, 2021): 143. http://dx.doi.org/10.12688/f1000research.40668.1.

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Ribosomal profiling is an emerging experimental technology to measure protein synthesis by sequencing short mRNA fragments undergoing translation in ribosomes. Applied on the genome wide scale, this is a powerful tool to profile global protein synthesis within cell populations of interest. Such information can be utilized for biomarker discovery and detection of treatment-responsive genes. However, analysis of ribosomal profiling data requires careful preprocessing to reduce the impact of artifacts and dedicated statistical methods for visualizing and modeling the high-dimensional discrete read count data. Here we present Ribosomal Profiling Reports (RP-REP), a new open-source cloud-enabled software that allows users to execute start-to-end gene-level ribosomal profiling and RNA-Seq analysis on a pre-configured Amazon Virtual Machine Image (AMI) hosted on AWS or on the user’s own Ubuntu Linux server. The software works with FASTQ files stored locally, on AWS S3, or at the Sequence Read Archive (SRA). RP-REP automatically executes a series of customizable steps including filtering of contaminant RNA, enrichment of true ribosomal footprints, reference alignment and gene translation quantification, gene body coverage, CRAM compression, reference alignment QC, data normalization, multivariate data visualization, identification of differentially translated genes, and generation of heatmaps, co-translated gene clusters, enriched pathways, and other custom visualizations. RP-REP provides functionality to contrast RNA-SEQ and ribosomal profiling results, and calculates translational efficiency per gene. The software outputs a PDF report and publication-ready table and figure files. As a use case, we provide RP-REP results for a dengue virus study that tested cytosol and endoplasmic reticulum cellular fractions of human Huh7 cells pre-infection and at 6 h, 12 h, 24 h, and 40 h post-infection. Case study results, Ubuntu installation scripts, and the most recent RP-REP source code are accessible at GitHub. The cloud-ready AMI is available at AWS (AMI ID: RPREP RSEQREP (Ribosome Profiling and RNA-Seq Reports) v2.1 (ami-00b92f52d763145d3)).
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4

Pan, Peipei, and Frank van Breukelen. "Preference of IRES-mediated initiation of translation during hibernation in golden-mantled ground squirrels, Spermophilus lateralis." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 301, no. 2 (August 2011): R370—R377. http://dx.doi.org/10.1152/ajpregu.00748.2010.

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Mammalian hibernation involves virtual cessation of energetically consumptive processes normally vital to homeostasis, including gene transcription and protein synthesis. As animals enter torpor, the bulk of initiation of translation is blocked at a body temperature of 18°C in golden-mantled ground squirrels [ Spermophilus (Callospermophilus) lateralis ]. Previous data demonstrated regulation of cap-dependent initiation of translation during torpor. We asked what happens to cap-independent, specifically, internal ribosome entry site (IRES)-mediated initiation of translation during hibernation. We analyzed polysome fractions for mRNAs that are known to contain or not to contain IRES elements. Here, we show that mRNAs harboring IRES elements preferentially associate with ribosomes as a torpor bout progresses. Squirrels allowed to naturally complete a torpor cycle have a higher IRES preference index than those animals that are prematurely aroused from torpor. Data indicate that this change in preference is not associated with gene expression, i.e., change is due to change in mRNA association with ribosomes as opposed to mRNA abundance. Thus, although processes like transcription and translation are virtually arrested during torpor, ribosomes are preferentially loaded with IRES-containing transcripts when squirrels arouse from torpor and translation resumes. Differential translation of preexisting mRNAs may allow for the preferential production of key stress proteins critical for survival of physiological insults that are lethal to other mammals.
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5

Wernersson, R. "Virtual Ribosome--a comprehensive DNA translation tool with support for integration of sequence feature annotation." Nucleic Acids Research 34, Web Server (July 1, 2006): W385—W388. http://dx.doi.org/10.1093/nar/gkl252.

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6

Martín-Villamil, María, Isaías Sanmartín, Ángela Moreno, and José Gallego. "Pharmacophore-Based Discovery of Viral RNA Conformational Modulators." Pharmaceuticals 15, no. 6 (June 14, 2022): 748. http://dx.doi.org/10.3390/ph15060748.

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New RNA-binding small-molecule scaffolds are needed to unleash the pharmacological potential of RNA targets. Here we have applied a pharmacophore-based virtual screening approach, seldom used in the RNA recognition field, to identify novel conformational inhibitors of the hepatitis C virus internal ribosome entry site. The conformational effect of the screening hits was assessed with a fluorescence resonance energy transfer assay, and the affinity, specificity, and binding site of the ligands were determined using a combination of fluorescence intensity and NMR spectroscopy experiments. The results indicate that this strategy can be successfully applied to discover RNA conformational inhibitors bearing substantially less positive charge than the reference ligands. This methodology can potentially be accommodated to other RNA motifs of pharmacological interest, facilitating the discovery of novel RNA-targeted molecules.
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7

Kumar, RBarani, and MXavier Suresh. "A computational perspective of molecular interactions through virtual screening, pharmacokinetic and dynamic prediction on ribosome toxin A chain and inhibitors of Ricinus communis." Pharmacognosy Research 4, no. 1 (2012): 2. http://dx.doi.org/10.4103/0974-8490.91027.

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8

Tam, Benjamin, Dror Sherf, Shira Cohen, Sarah Adi Eisdorfer, Moshe Perez, Adam Soffer, Dan Vilenchik, Sabine Ruth Akabayov, Gerhard Wagner, and Barak Akabayov. "Discovery of small-molecule inhibitors targeting the ribosomal peptidyl transferase center (PTC) of M. tuberculosis." Chemical Science 10, no. 38 (2019): 8764–67. http://dx.doi.org/10.1039/c9sc02520k.

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9

Kumari, Sweta, Arumugam Mohana Priya, Sajitha Lulu, and Mohammad Tauqueer. "Molecular modeling, simulation and virtual screening of ribosomal phosphoprotein P1 from Plasmodium falciparum." Journal of Theoretical Biology 343 (February 2014): 113–19. http://dx.doi.org/10.1016/j.jtbi.2013.10.014.

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10

Turgeon, Zachari, René Jørgensen, Danielle Visschedyk, Patrick R. Edwards, Sarah Legree, Caroline McGregor, Robert J. Fieldhouse, Dev Mangroo, Matthieu Schapira, and A. Rod Merrill. "Newly Discovered and Characterized Antivirulence Compounds Inhibit Bacterial Mono-ADP-Ribosyltransferase Toxins." Antimicrobial Agents and Chemotherapy 55, no. 3 (December 6, 2010): 983–91. http://dx.doi.org/10.1128/aac.01164-10.

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ABSTRACTThe mono-ADP-ribosyltransferase toxins are bacterial virulence factors that contribute to many disease states in plants, animals, and humans. These toxins function as enzymes that target various host proteins and covalently attach an ADP-ribose moiety that alters target protein function. We tested compounds from a virtual screen of commercially available compounds combined with a directed poly(ADP-ribose) polymerase (PARP) inhibitor library and found several compounds that bind tightly and inhibit toxins fromPseudomonas aeruginosaandVibrio cholerae. The most efficacious compounds completely protected human lung epithelial cells against the cytotoxicity of these bacterial virulence factors. Moreover, we determined high-resolution crystal structures of the best inhibitors in complex with cholix toxin to reveal important criteria for inhibitor binding and mechanism of action. These results provide new insight into development of antivirulence compounds for treating many bacterial diseases.
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11

Maia, Mayara dos Santos, Francisco Jaime Bezerra Mendonça-Junior, Gabriela Cristina Soares Rodrigues, Adriano Soares da Silva, Niara Isis Pereira de Oliveira, Pablo Rayff da Silva, Cícero Francisco Bezerra Felipe, et al. "Virtual Screening of Different Subclasses of Lignans with Anticancer Potential and Based on Genetic Profile." Molecules 28, no. 16 (August 11, 2023): 6011. http://dx.doi.org/10.3390/molecules28166011.

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Cancer is a multifactorial disease that continues to increase. Lignans are known to be important anticancer agents. However, due to the structural diversity of lignans, it is difficult to associate anticancer activity with a particular subclass. Therefore, the present study sought to evaluate the association of lignan subclasses with antitumor activity, considering the genetic profile of the variants of the selected targets. To do so, predictive models were built against the targets tyrosine-protein kinase ABL (ABL), epidermal growth factor receptor erbB1 (EGFR), histone deacetylase (HDAC), serine/threonine-protein kinase mTOR (mTOR) and poly [ADP-ribose] polymerase-1 (PARP1). Then, single nucleotide polymorphisms were mapped, target mutations were designed, and molecular docking was performed with the lignans with the best predicted biological activity. The results showed more anticancer activity in the dibenzocyclooctadiene, furofuran and aryltetralin subclasses. The lignans with the best predictive values of biological activity showed varying binding energy results in the presence of certain genetic variants.
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12

Al-Sanea, Mohammad M., Garri Chilingaryan, Narek Abelyan, Michael Mamikonyan, Hayk Gasparyan, Sargis Hovhannisyan, Abdelrahman Hamdi, Ahmed R. Ali, Samy Selim, and Ahmed A. B. Mohamed. "Combination of ligand and structure based virtual screening approaches for the discovery of potential PARP1 inhibitors." PLOS ONE 17, no. 9 (September 12, 2022): e0272065. http://dx.doi.org/10.1371/journal.pone.0272065.

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Poly (ADP-ribose) polymerase 1 (PARP1) has high therapeutic value as biomolecular target for research and development of small molecules with antineoplastic activity, since it is upregulated in many cancers, especially in ovarian and BRCA 1/2 mutated breast cancers. Decades of investigation of PARP inhibitors (PARPi) have led to the approval of several drug compounds, however clinical application of PARPi in cancer therapy is limited due to a number of factors, including low selectivity, weak affinity and undesired side effects. Thus, identification of novel drug-like chemical compounds with alternatives to the known PARPi chemical scaffolds, binding modes and interaction patterns with amino acid residues in the active site is of high therapeutic importance. In this study we applied a combination of ligand- and structure-based virtual screening approaches with the goal of identification of novel potential PARPi.
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13

Alvarado, Pablo, and Jose L. Manjón. "Selection of Enzymes for Terminal Restriction Fragment Length Polymorphism Analysis of Fungal Internally Transcribed Spacer Sequences." Applied and Environmental Microbiology 75, no. 14 (May 22, 2009): 4747–52. http://dx.doi.org/10.1128/aem.00568-09.

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ABSTRACT Terminal restriction fragment length polymorphism (TRFLP) profiling of the internally transcribed spacer (ITS) ribosomal DNA of unknown fungal communities is currently unsupported by a broad-range enzyme-choosing rationale. An in silico study of terminal fragment size distribution was therefore performed following virtual digestion (by use of a set of commercially available 135 type IIP restriction endonucleases) of all published fungal ITS sequences putatively annealing to primers ITS1 and ITS4. Different diversity measurements were used to rank primer-enzyme pairs according to the richness and evenness that they showed. Top-performing pairs were hierarchically clustered to test for data dependency. The enzyme set composed of MaeII, BfaI, and BstNI returned much better results than randomly chosen enzyme sets in computer simulations and is therefore recommended for in vitro TRFLP profiling of fungal ITSs.
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14

Khalil, Mohammad Ibrahim. "Identification of Cladosporium sp. Fungi by in- silico RFLP-PCR." Baghdad Science Journal 17, no. 1(Suppl.) (March 18, 2020): 0220. http://dx.doi.org/10.21123/bsj.2020.17.1(suppl.).0220.

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Cladosporium sp. plays an important role in human health, it is one of the pathogenic fungi which cause allergy and asthma and most frequently isolated from airborne spores. In this study, a couple of universal PCR primers were designed to identify the pathogenic fungi Cladosporium sp. according to conserved region 5.8S, 18S and 28S subunit ribosomal RNA gene in Cladosporium species. In silico RFLP-PCR were used to identify twenty-four Cladosporium strains. The results showed that the universal primer has the specificity to amplify the conserved region in 24 species as a band in virtual agarose gel. They also showed that the RFLP method is able to identify three Cladosporium species by specific and unique restriction enzymes for each one. These species are Cl. halotorenas by the two unique enzymes BsaXI and MobII, the other species is Cl. colrandse by two enzymes BccI and BtsCI, while the third species is Cl. aciculare by one enzyme BceAI. Each enzyme forms two bands in virtual agarose gel as a results of cutting the DNA by the enzyme, where the rest twenty – two species share more than one restriction enzymes. This method is active and rapid for identifying Cladosporium genus and three species by computational bases methods before applying it in the lab for more accuracy, efficiency, and specificity of designed primer to get good results in a short time.
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Park, So-Jung, Yang-Gyun Kim, and Hyun-Ju Park. "Identification of RNA Pseudoknot-Binding Ligand That Inhibits the −1 Ribosomal Frameshifting of SARS-Coronavirus by Structure-Based Virtual Screening." Journal of the American Chemical Society 133, no. 26 (July 6, 2011): 10094–100. http://dx.doi.org/10.1021/ja1098325.

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Park, So-Jung, Yang-Gyun Kim, and Hyun-Ju Park. "Identification of RNA Pseudoknot-Binding Ligand That Inhibits the −1 Ribosomal Frameshifting of SARS-Coronavirus by Structure-Based Virtual Screening." Journal of the American Chemical Society 133, no. 35 (September 7, 2011): 14150. http://dx.doi.org/10.1021/ja206172p.

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17

Lee, I. M., K. D. Bottner-Parker, Y. Zhao, A. Bertaccini, and R. E. Davis. "Differentiation and classification of phytoplasmas in the pigeon pea witches’-broom group (16SrIX): an update based on multiple gene sequence analysis." International Journal of Systematic and Evolutionary Microbiology 62, Pt_9 (September 1, 2012): 2279–85. http://dx.doi.org/10.1099/ijs.0.038273-0.

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The pigeon pea witches’-broom phytoplasma group (16SrIX) comprises diverse strains that cause numerous diseases in leguminous trees and herbaceous crops, vegetables, a fruit, a nut tree and a forest tree. At least 14 strains have been reported worldwide. Comparative phylogenetic analyses of the highly conserved 16S rRNA gene and the moderately conserved rplV (rpl22)–rpsC (rps3) and secY genes indicated that the 16SrIX group consists of at least six distinct genetic lineages. Some of these lineages cannot be readily differentiated based on analysis of 16S rRNA gene sequences alone. The relative genetic distances among these closely related lineages were better assessed by including more variable genes [e.g. ribosomal protein (rp) and secY genes]. The present study demonstrated that virtual RFLP analyses using rp and secY gene sequences allowed unambiguous identification of such lineages. A coding system is proposed to designate each distinct rp and secY subgroup in the 16SrIX group.
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18

Azeem, Muhammad, Ghulam Mustafa, and Hafiza S. Mahrosh. "Virtual screening of phytochemicals by targeting multiple proteins of severe acute respiratory syndrome coronavirus 2: Molecular docking and molecular dynamics simulation studies." International Journal of Immunopathology and Pharmacology 36 (January 2022): 039463202211427. http://dx.doi.org/10.1177/03946320221142793.

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Objective Medicinal herbs are being investigated for medicationhg development against SARS-CoV-2 as a rich source of bioactive chemicals. One of the finest approaches for finding therapeutically effective drug molecules in real time is virtual screening scheme such as molecular docking in conjunction with molecular dynamics (MD) simulation. These virtual techniques provide an ample opportunity for the screening of plausible inhibitors of SARS-CoV-2 different target proteins from a comprehensive and extensive phytochemical library. The study was designed to identify potential phytochemicals by virtual screening against different receptor proteins. Methods In the current study, a library of plant secondary metabolites was created by manually curating 120 phytochemicals known to have antimicrobial as well as antiviral properties. In the current study, different potential phytochemicals were identified by virtual screening against various selected receptor proteins (i.e., viral main proteases, RNA-dependent RNA polymerase (RdRp), ADP ribose phosphatase, nonstructural proteins NSP7, NSP8, and NSP9) which are key proteins responsible for transcription, replication and maturation of SARS-CoV-2 in the host. Top three phytochemicals were selected against each viral receptor protein based on their best S-scores, RMSD values, molecular interactions, binding patterns and drug-likeness properties. Results The results of molecular docking study revealed that phytochemicals (i.e., baicalin, betaxanthin, epigallocatechin, fomecin A, gallic acid, hortensin, ichangin, kaempferol, limonoic acid, myricetin hexaacetat, pedalitin, quercetin, quercitrin, and silvestrol) have strong antiviral potential against SARS-CoV-2. Additionally, the reported preeminent reliable phytochemicals also revealed toxicity by no means during the evaluation through ADMET profiling. Moreover, the MD simulation study also exhibited thermal stability and stable binding affinity of the pedalitin with SARS-CoV-2 RdRp and SARS-CoV-2 main protease which suggests appreciable efficacy of the lead optimization. Conclusion The biological activity and pharmacologically distinguishing characteristics of these lead compounds also satisfied as repurposing antiviral drug contenders and are worth substantial evaluation in the biological laboratory for the recommendation of being plausible antiviral drug candidates against SARS-CoV-2.
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Ryu, Hwani, Hye-Ran Seo, Hyo Jeong Kim, and Jiyeon Ahn. "Abstract 521: Discovery of novel TNKS inhibitors through structure-based virtual screening." Cancer Research 83, no. 7_Supplement (April 4, 2023): 521. http://dx.doi.org/10.1158/1538-7445.am2023-521.

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Abstract More than 80% of colorectal cancers (CRCs) have somatic mutations in the adenomatous polyposis coli (APC) gene, which affects abnormal WNT/β-catenin signaling. Since inhibition of tankyrases (TNKS1 and TNKS2) belonging to the poly(ADP-ribose) polymerase family stabilizes AXINs and induces degradation of β-catenin, drug development as a therapeutic target for APC-mutated CRCs is required. To identify selective small molecule inhibitors of TNKS, we performed pharmacophore modeling and structural docking studies targeting nicotinamide, adenosine, and both binding subsites of TNKS. Among the 8 million compounds, 149 of the nicotinamide site binders, 23 of the adenosine site binders, and 15 of the dual-site binders of TNKS were selected through computer-based virtual screening. Using in vitro TNKS1 and TNKS2 enzyme assays, we identified that TI2-N17 and TI3-D11 significantly inhibited TNKS1 and TNKS2 enzyme activities at low nanomolar levels. TI2-N17 and TI3-D11 stabilized AXIN2, reduced active β-catenin, and downregulated β-catenin target genes in COLO320DM, APC-mutated CRC cells. Both compounds exhibited anticancer effects on COLO320DM and SW403 cells. In addition, the combination treatment of 5-Fluorouracil (5-FU), an anticancer agent for CRC patients, and these compounds synergistically inhibited the proliferation of CRC cells compared to single compound treatment. Our findings demonstrated that TI2-N17 and TI3-D11 are therapeutic candidates targeting TNKS for APC-mutated CRCs treatment and suggested that the combined treatment with the compounds and 5-FU chemotherapy may be an effective therapeutic strategy for APC-mutated CRCs. Based on these compounds, further study will develop potent and selective TNKS inhibitors by designing and synthesizing novel derivative compounds. Citation Format: Hwani Ryu, Hye-Ran Seo, Hyo Jeong Kim, Jiyeon Ahn. Discovery of novel TNKS inhibitors through structure-based virtual screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 521.
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20

Zhao, Yue, Rui-fang Chen, Zhen-Ke Deng, Liu-Xia Zhang, Yan Cheng, Alex F. Chen, and Dong-Sheng Cao. "Discovery of novel p90 ribosomal S6 kinase 2 inhibitors for potential cancer treatment through ligand-based and structure-based virtual screening methods." Chemometrics and Intelligent Laboratory Systems 217 (October 2021): 104402. http://dx.doi.org/10.1016/j.chemolab.2021.104402.

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21

Li, Shiliang, Yi Zhou, Weiqiang Lu, Ye Zhong, Wenlong Song, Kangdong Liu, Jin Huang, et al. "Identification of Inhibitors against p90 Ribosomal S6 Kinase 2 (RSK2) through Structure-Based Virtual Screening with the Inhibitor-Constrained Refined Homology Model." Journal of Chemical Information and Modeling 51, no. 11 (October 21, 2011): 2939–47. http://dx.doi.org/10.1021/ci2002445.

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22

Kumari, Sweta, Arumugam MohanaPriya, Sajitha Lulu, and Mohammad Tauqueer. "Corrigendum to “Molecular modeling, simulation and virtual screening of ribosomal phosphoprotein P1 from Plasmodium falciparum” [J. Theor. Biol. 343 (2014) 113–119]." Journal of Theoretical Biology 354 (August 2014): 146. http://dx.doi.org/10.1016/j.jtbi.2014.04.001.

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23

Saks, Ülle, John Davison, Maarja Öpik, Martti Vasar, Mari Moora, and Martin Zobel. "Root-colonizing and soil-borne communities of arbuscular mycorrhizal fungi in a temperate forest understorey." Botany 92, no. 4 (April 2014): 277–85. http://dx.doi.org/10.1139/cjb-2013-0058.

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We analyzed arbuscular mycorrhizal fungal (AMF) communities in plant root samples from a natural forest ecosystem — a primeval forest in Järvselja, Estonia. AMF small-subunit (SSU) ribosomal RNA genes were subjected to 454-pyrosequencing and BLAST-based taxonomic identification. Seventy-six AMF sequence groups (virtual taxa, VT) were identified from plant roots. Taken together with seven additional VT recorded in an earlier investigation of soil AMF communities at the site, this represents the highest number of AMF reported from a single ecosystem to date. The six study plant species hosted similar AMF communities. However, AMF community composition in plant roots was significantly different from that in soil and considerably more VT were retrieved from roots than from soil. AMF VT identified from plant roots as a whole and from individual plant species were frequently phylogenetically clustered compared with local and global taxon pools, suggesting that nonrandom assembly processes, notably habitat filtering, may have shaped fungal assemblages. In contrast, the phylogenetic dispersion of AMF communities in soil did not differ from random subsets of the local or global taxon pools.
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Gaafar, Yahya Z. A., Marcel Westenberg, Marleen Botermans, Krizbai László, Kris De Jonghe, Yoika Foucart, Luca Ferretti, et al. "Interlaboratory Comparison Study on Ribodepleted Total RNA High-Throughput Sequencing for Plant Virus Diagnostics and Bioinformatic Competence." Pathogens 10, no. 9 (September 12, 2021): 1174. http://dx.doi.org/10.3390/pathogens10091174.

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High-throughput sequencing (HTS) technologies and bioinformatic analyses are of growing interest to be used as a routine diagnostic tool in the field of plant viruses. The reliability of HTS workflows from sample preparation to data analysis and results interpretation for plant virus detection and identification must be evaluated (verified and validated) to approve this tool for diagnostics. Many different extraction methods, library preparation protocols, and sequence and bioinformatic pipelines are available for virus sequence detection. To assess the performance of plant virology diagnostic laboratories in using the HTS of ribosomal RNA depleted total RNA (ribodepleted totRNA) as a diagnostic tool, we carried out an interlaboratory comparison study in which eight participants were required to use the same samples, (RNA) extraction kit, ribosomal RNA depletion kit, and commercial sequencing provider, but also their own bioinformatics pipeline, for analysis. The accuracy of virus detection ranged from 65% to 100%. The false-positive detection rate was very low and was related to the misinterpretation of results as well as to possible cross-contaminations in the lab or sequencing provider. The bioinformatic pipeline used by each laboratory influenced the correct detection of the viruses of this study. The main difficulty was the detection of a novel virus as its sequence was not available in a publicly accessible database at the time. The raw data were reanalysed using Virtool to assess its ability for virus detection. All virus sequences were detected using Virtool in the different pools. This study revealed that the ribodepletion target enrichment for sample preparation is a reliable approach for the detection of plant viruses with different genomes. A significant level of virology expertise is needed to correctly interpret the results. It is also important to improve and complete the reference data.
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Zhou, Yunjiang, Shi Tang, Tingting Chen, and Miao-Miao Niu. "Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking and Biological Evaluation for Identification of Potential Poly (ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors." Molecules 24, no. 23 (November 22, 2019): 4258. http://dx.doi.org/10.3390/molecules24234258.

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Poly (ADP-ribose) polymerase-1 (PARP-1) plays critical roles in many biological processes and is considered as a potential target for anticancer therapy. Although some PARP-1 inhibitors have been reported, their clinical application in cancer therapy is limited by some shortcomings such as weak affinity, low selectivity and adverse side effects. To identify highly potent and selective PARP-1 inhibitors, an integrated protocol that combines pharmacophore mapping, virtual screening and molecular docking was constructed. It was then used as a screening query to identify potent leads with unknown scaffolds from an in-house database. Finally, four retrieved compounds were selected for biological evaluation. Biological testing indicated that the four compounds showed strong inhibitory activities on the PARP-1 (IC50 < 0.2 μM). MTT assay confirmed that compounds 1–4 inhibited the growth of human lung cancer A549 cells in a dose-dependent manner. The obtained compounds from this study may be potential leads for PARP-1 inhibition in the treatment of cancer.
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Virdi, Rajdeep S., Robert V. Bavisotto, Nicholas C. Hopper, Nemanja Vuksanovic, Trevor R. Melkonian, Nicholas R. Silvaggi, and David N. Frick. "Discovery of Drug-Like Ligands for the Mac1 Domain of SARS-CoV-2 Nsp3." SLAS DISCOVERY: Advancing the Science of Drug Discovery 25, no. 10 (September 28, 2020): 1162–70. http://dx.doi.org/10.1177/2472555220960428.

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Small molecules that bind the SARS-CoV-2 nonstructural protein 3 Mac1 domain in place of ADP-ribose could be useful as molecular probes or scaffolds for COVID-19 antiviral drug discovery because Mac1 has been linked to the ability of coronaviruses to evade cellular detection. A high-throughput assay based on differential scanning fluorimetry (DSF) was therefore optimized and used to identify possible Mac1 ligands in small libraries of drugs and drug-like compounds. Numerous promising compounds included nucleotides, steroids, β-lactams, and benzimidazoles. The main drawback to this approach was that a high percentage of compounds in some libraries were found to influence the observed Mac1 melting temperature. To prioritize DSF screening hits, the shapes of the observed melting curves and initial assay fluorescence were examined, and the results were compared with virtual screens performed using AutoDock Vina. The molecular basis for alternate ligand binding was also examined by determining a structure of one of the hits, cyclic adenosine monophosphate, with atomic resolution.
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Haitham Al-Madhagi and Hisham Al-Ward. "New Inhibitors of Glucose-6-Phosphate Dehydrogenase Discovered by Molecular Docking." East Asian Journal of Multidisciplinary Research 1, no. 9 (October 29, 2022): 1793–800. http://dx.doi.org/10.55927/eajmr.v1i9.1191.

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The aim of this study is to in silico screen new glucose-6-phosphate dehydrogenase (G6PD) inhibitors. glucose-6-phosphate dehydrogenase is the first and regulator of pentose phosphate pathway providing NADPH and ribose-5-phosphate required for various syntheses from fatty acids to DNA. G6PD is linked to oxidative stress and hence, to inflammation as well. Therefore, G6PD inhibition is a useful target against inflammation, cancer and some infections. Virtual screening of 15 ligands in the NADP-binding site in comparison with the standard inhibitor 6-aminonicotinamide using iGEMDOCK. Besides, ADME properties of the selected compounds were performed via SWISSADME webserver. All the tested ligands were better than reference inhibitor in terms of binding energy as well as pharmacokinetic and ADME parameters. Moreover, of all tested compounds, ligand 15 showed best docking fitness (-115 Kcal/mole total energy). Novel compounds were screened to be lead inhibitors of G6PD enzyme and ligand 15 ranked first.
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Patel, Dhrumi C., Katherine R. Hausman, Muhammad Arba, Annie Tran, Phillip M. Lakernick, and Chun Wu. "Novel inhibitors to ADP ribose phosphatase of SARS-CoV-2 identified by structure-based high throughput virtual screening and molecular dynamics simulations." Computers in Biology and Medicine 140 (January 2022): 105084. http://dx.doi.org/10.1016/j.compbiomed.2021.105084.

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Frederiks, Wilma M., Intan P. E. D. Kümmerlin, Klazina S. Bosch, Heleen Vreeling-Sindelárová, Ard Jonker, and Cornelis J. F. Van Noorden. "NADPH Production by the Pentose Phosphate Pathway in the Zona Fasciculata of Rat Adrenal Gland." Journal of Histochemistry & Cytochemistry 55, no. 9 (May 3, 2007): 975–80. http://dx.doi.org/10.1369/jhc.7a7222.2007.

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Biosynthesis of steroid hormones in the cortex of the adrenal gland takes place in smooth endoplasmic reticulum and mitochondria and requires NADPH. Four enzymes produce NADPH: glucose-6-phosphate dehydrogenase (G6PD), the key regulatory enzyme of the pentose phosphate pathway, phosphogluconate dehydrogenase (PGD), the third enzyme of that pathway, malate dehydrogenase (MDH), and isocitrate dehydrogenase (ICDH). However, the contribution of each enzyme to NADPH production in the cortex of adrenal gland has not been established. Therefore, activity of G6PD, PGD, MDH, and ICDH was localized and quantified in rat adrenocortical tissue using metabolic mapping, image analysis, and electron microscopy. The four enzymes have similar localization patterns in adrenal gland with highest activities in the zona fasciculata of the cortex. G6PD activity was strongest, PGD, MDH, and ICDH activity was ∼60%, 15%, and 7% of G6PD activity, respectively. The Km value of G6PD for glucose-6-phosphate was two times higher than the Km value of PGD for phosphogluconate. As a consequence, virtual flux rates through G6PD and PGD are largely similar. It is concluded that G6PD and PGD provide the major part of NADPH in adrenocortical cells. Their activity is localized in the cytoplasm associated with free ribosomes and membranes of the smooth endoplasmic reticulum, indicating that NADPH-demanding processes related to biosynthesis of steroid hormones take place at these sites. Complete inhibition of G6PD by androsterones suggests that there is feedback regulation of steroid hormone biosynthesis via G6PD.
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Garcia-Moran, Emilio, Marta Hernández, David Abad, and José M. Eiros. "Putative Secondary Structure at 5’UTR as a Potential Antiviral Target against SARS-CoV-2." Revista Española de Quimioterapia 35, no. 2 (December 15, 2021): 204–12. http://dx.doi.org/10.37201/req/153.2021.

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SARS-CoV-2 is an enveloped positive-sense single-stranded RNA coronavirus that causes COVID-19, of which the current outbreak has resulted in a high number of cases and fatalities throughout the world, even vaccine doses are being administered. The aim of this work was to scan the SARS-CoV-2 genome in search for therapeutic targets. We found a sequence in the 5’UTR (NC 045512:74-130), consisting of a typical heptamer next to a structured region that may cause ribosomal frameshifting. The potential biological value of this region is relevant through its low similarity with other viruses, including coronaviruses related to SARS-CoV, and its high sequence conservation within multiple SARS-CoV-2 isolates. We have predicted the secondary structure of the region by means of different bioinformatic tools. We have suggested a most probable secondary structure to proceed with a 3D reconstruction of the structured segment. Finally, we carried out virtual docking on the 3D structure to look for a binding site and then for drug ligands from a database of lead compounds. Several molecules that could be probably administered as oral drugs show promising binding affinity within the structured region, and so it could be possible interfere its potential regulatory role.
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Heliot, Laurent, Hervé Kaplan, Laurent Lucas, Christophe Klein, Adrien Beorchia, Martine Doco-Fenzy, Monique Menager, Marc Thiry, Marie-Françoise O’Donohue, and Dominique Ploton. "Electron Tomography of Metaphase Nucleolar Organizer Regions: Evidence for a Twisted-Loop Organization." Molecular Biology of the Cell 8, no. 11 (November 1997): 2199–216. http://dx.doi.org/10.1091/mbc.8.11.2199.

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Metaphase nucleolar organizer regions (NORs), one of four types of chromosome bands, are located on human acrocentric chromosomes. They contain r-chromatin, i.e., ribosomal genes complexed with proteins such as upstream binding factor and RNA polymerase I, which are argyrophilic NOR proteins. Immunocytochemical and cytochemical labelings of these proteins were used to reveal r-chromatin in situ and to investigate its spatial organization within NORs by confocal microscopy and by electron tomography. For each labeling, confocal microscopy revealed small and large double-spotted NORs and crescent-shaped NORs. Their internal three-dimensional (3D) organization was studied by using electron tomography on specifically silver-stained NORs. The 3D reconstructions allow us to conclude that the argyrophilic NOR proteins are grouped as a fiber of 60–80 nm in diameter that constitutes either one part of a turn or two or three turns of a helix within small and large double-spotted NORs, respectively. Within crescent-shaped NORs, virtual slices reveal that the fiber constitutes several longitudinally twisted loops, grouped as two helical 250- to 300-nm coils, each centered on a nonargyrophilic axis of condensed chromatin. We propose a model of the 3D organization of r-chromatin within elongated NORs, in which loops are twisted and bent to constitute one basic chromatid coil.
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Šeruga Musić, M., D. Škorić, I. Haluška, I. Križanac, J. Plavec, and I. Mikec. "First Report of Flavescence Dorée-Related Phytoplasma Affecting Grapevines in Croatia." Plant Disease 95, no. 3 (March 2011): 353. http://dx.doi.org/10.1094/pdis-09-10-0664.

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Flavescence dorée (FD) and Bois noir (BN) phytoplasmas are principal grapevine yellows (GY) agents in the wider Euro-Mediterranean Region. While BN phytoplasma belongs to the ribosomal subgroup 16SrXII-A, the FD agents belong either to the ribosomal subgroups 16SrV-C or -D. During the official GY survey in 2009, 40 symptomatic grapevines (Vitis vinifera L.) were sampled throughout grapevine-growing regions in Croatia. Typical GY symptoms of leaf yellowing or reddening were evident on white and red varieties, respectively. Leaf rolling as well as irregular lignification of the shoots and withering of clusters were also observed. Phloem tissue from cuttings and leaf veins from mature vines were sampled for total DNA extraction and amplification of phytoplasma 16S rRNA gene by using generic primers P1/P7 in a direct PCR assay followed by a nested PCR using primer pair R16F2n/R2 (2). Phytoplasma ribosomal group affiliation was determined by restriction fragment length polymorphism (RFLP) analysis of the nested PCR products with enzyme Tru1I (Fermentas, Vilnius, Lithuania). These initial findings were validated and augmented by a triplex real-time PCR assay targeting the nonribosomal map gene. This assay enables simultaneous detection of BN and FD (16SrV-C and -D) phytoplasmas in grapevine (3). Assay results revealed the majority of GY positive vines (19 of 40) contained BN phytoplasma which is widespread. For the first time in Croatia, two red variety samples, Pinot Noir and Plemenka Crvena, from the vicinity of Ozalj (Vivodina) and Zagreb (Brezje), respectively, were found to harbor FD-related phytoplasmas. Fragments amplified by P1/P7 primers from latter samples were cloned and sequenced. Sequence analyses using online interactive tool iPhyClassifier (4) revealed that the phytoplasma under study from Pinot Noir sample (GenBank Accession No. HQ712064) is a member of 16SrV-C subgroup and shares 99.87% similarity with 16S rDNA sequence of the reference strain (GenBank Accession No. AF176319). The sequence from the Plemenka Crvena sample (GenBank Accession No. HQ712065) shares 99.54% similarity with the reference strain and has the most similar virtual RFLP pattern to the one of the 16SrV-C subgroup (GenBank Accession No. AY197642). These findings are currently limited to vineyards in northwestern Croatia. Even so, the presence of FD principal cicadellid vector Scaphoideus titanus in the country and the occurrence and distribution of FD in neighboring countries (1,2) are factors indicating that the spread of FD in Croatia is highly probable. References: (1) L. Filippin et al. Plant Pathol. 58:826, 2009. (2) S. Kuzmanović et al. Vitis 47:105, 2008. (3) C. Pelletier et al. Vitis 48:87, 2009. (4) Y. Zhao et al. Int. J. Syst. Evol. Microbiol. 59:2582, 2009.
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S. Pai, K. Usha, Yadav D. Bodke, Suman Manandhar, and K. Sreedhara Ranganath Pai. "in silico-Based Virtual Screening and Molecular Docking Analysis of Phytochemicals obtained from Methanolic Extract of Cleome viscosa Linn. by GC-MS Method for its Anticancer Activity." Asian Journal of Chemistry 33, no. 12 (2021): 2943–52. http://dx.doi.org/10.14233/ajchem.2021.23384.

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Cleome viscosa belonging to the family Capparidaceae, is a weed with ethano-botanical value found in India. In the present investigation, methanolic extract of Cleome viscosa was analyzed by gas chromatography-mass spectrometry (GC-MS) to identify the important phytochemical constituents. The GC-MS analysis of methanol from whole plant of Cleome viscosa detected the presence of 78 phytochemical compounds. Quantitative phytochemical evaluation of the methanolic extract of Cleome viscosa was performed. These identified compounds were analyzed for their anticancer activity through in silico molecular docking studies. Computation based in silico docking studies were done using maestro interface. Three protein, poly (ADP-ribose) polymerase-1 (PARP-1), epidermal growth factor receptor (EGFR), human papilloma virus (HPV) specific to different cancers were selected for screening of these phytochemicals. Phytomolecules with better activity and binding were shortlisted after XP mode of docking. The dock score, glide energy and 2D binding interactions of the top five phytochemicals with three selected proteins have been discussed. The identified hit could be a potent inhibitor these proteins that further requires experimental validation.
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Zheng, Lufeng, Ren Ren, Xiaolian Sun, Yunting Zou, Yiru Shi, Bin Di, and Miao-Miao Niu. "Discovery of a Dual Tubulin and Poly(ADP-Ribose) Polymerase-1 Inhibitor by Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking, and Biological Evaluation." Journal of Medicinal Chemistry 64, no. 21 (October 21, 2021): 15702–15. http://dx.doi.org/10.1021/acs.jmedchem.1c00932.

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35

Haug, Ingeborg, Sabrina Setaro, and Juan Pablo Suárez. "Global AM fungi are dominating mycorrhizal communities in a tropical premontane dry forest in Laipuna, South Ecuador." Mycological Progress 20, no. 6 (June 2021): 837–45. http://dx.doi.org/10.1007/s11557-021-01699-4.

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AbstractTropical dry forests are an intricate ecosystem with special adaptations to periods of drought. Arbuscular mycorrhizal fungi (AMF) are essential for plant survival in all terrestrial ecosystems but might be of even greater importance in dry forests as plant growth is limited due to nutrient and water deficiency during the dry season. Tropical dry forests in Ecuador are highly endangered, but studies about AMF communities are scarce. We investigated the AMF community of a premontane semi-deciduous dry forest in South Ecuador during the dry season. We estimated AMF diversity, distribution, and composition of the study site based on operational taxonomic units (OTUs) and compared the results to those from the tropical montane rainforest and páramo in South Ecuador. OTU delimitation was based on part of the small ribosomal subunit obtained by cloning and Sanger sequencing. Nearly all OTUs were Glomeraceae. The four frequent OTUs were Glomus, and comparison with the MaarjAM database revealed these to be globally distributed with a wide range of ecological adaptations. Several OTUs are shared with virtual taxa from dry forests in Africa. Ordination analysis of AMF communities from the tropical dry and montane rainforests in South Ecuador revealed a unique AMF community in the dry forest with only few overlapping OTUs. Most OTUs that were found in both dry and rainforests and on the two continents were globally distributed Glomus.
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Morales, Paula, Natalie Curtis, Sandra Zárate, Agatha Bastida, and Victor Bolanos-Garcia. "Interfering with mRNA Methylation by the 2′O-Methyltransferase (NSP16) from SARS-CoV-2 to Tackle the COVID-19 Disease." Catalysts 10, no. 9 (September 5, 2020): 1023. http://dx.doi.org/10.3390/catal10091023.

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The pandemic associated to Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2) has resulted in a huge number of deaths and infected people. Although several vaccine programmes are currently underway and have reached phase 3, and a few small size drugs repurposed to aid treatment of severe cases of COVID-19 infections, effective therapeutic options for this disease do not currently exist. NSP16 is a S-adenosyl-L-Methionine (SAM) dependent 2′O-Methyltransferase that converts mRNA cap-0 into cap-1 structure to prevent virus detection by cell innate immunity mechanisms. NSP16 methylates the ribose 2′O-position of the first nucleotide of the mRNA only in the presence of an interacting partner, the protein NSP10. This feature suggests that inhibition of the NSP16 may represent a therapeutic window to treat COVID-19. To test this idea, we performed comparative structural analyses of the NSP16 present in human coronaviruses and developed a sinefungin (SFG) similarity-based virtual screening campaign to assess the druggability of the SARS-CoV-2 NSP16 enzyme. Through these studies, we identified the SFG analogue 44601604 as a promising more potent inhibitor of NSP16 to limit viral replication in infected cells, favouring viral clearance.
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Usta, Mustafa, Abdullah Güller, and Hikmet Murat Sipahioğlu. "First report of 'Candidatus Phytoplasma trifolii' associated with leaf reddening and upright growth in pears (Pyrus communis L.)." Plant Protection Science 57, No. 3 (June 10, 2021): 188–95. http://dx.doi.org/10.17221/163/2020-pps.

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The natural occurrence of 'Candidatus Phytoplasma trifolii' in pear trees (Pyrus communis Linnaeus) is reported here for the first time. In 2017, a total of thirty-five pear trees, two of them exhibiting leaf rolling along the midvein, reddening, bushy appearance, and upright growth symptoms were sampled in different locations in Van province, Turkey. The total deoxyribonucleic acid was extracted from symptomatic and asymptomatic plants. The purified DNA served as a template in nested polymerase chain reaction (nested-PCR) assays, performed to amplify 16S rRNA sequences using universal primer pairs (R16mF2/R16mR1 and R16F2n/R16R2). The resulting PCR products were then cloned into a pGEM T-Easy vector and sequenced bidirectionally. The phytoplasma strain, group, and subgroup identity were determined using the in silico restriction fragment length polymorphism (RFLP) analysis of the 16S ribosomal RNA-encoding gene sequences profiling with seventeen distinct restriction enzymes. Of the thirty-five pear samples, only two yielded 1 256 bp and 1 258 bp DNA fragments and were designated as Van-Pr3 (Acc. No. MH709141) and Van-Pr4 (Acc. No. MH730561), respectively. Based on the in silico virtual RFLP pattern analysis of the 16S rRNA sequences, we confirmed the presence of 'Ca. P. trifolii' belonging to the clover proliferation group and both identified phytoplasmas were identical with the similarity coefficient of 1.00 to the reference pattern of 16Sr group VI, subgroup A (Acc. No. AY390261). Here we report that the pear tree is an alternate host of the 'Ca. P. trifolii'.
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Doronina, Liliya, Olga Reising, and Jürgen Schmitz. "Gene Conversion amongst Alu SINE Elements." Genes 12, no. 6 (June 11, 2021): 905. http://dx.doi.org/10.3390/genes12060905.

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The process of non-allelic gene conversion acts on homologous sequences during recombination, replacing parts of one with the other to make them uniform. Such concerted evolution is best described as paralogous ribosomal RNA gene unification that serves to preserve the essential house-keeping functions of the converted genes. Transposed elements (TE), especially Alu short interspersed elements (SINE) that have more than a million copies in primate genomes, are a significant source of homologous units and a verified target of gene conversion. The consequences of such a recombination-based process are diverse, including multiplications of functional TE internal binding domains and, for evolutionists, confusing divergent annotations of orthologous transposable elements in related species. We systematically extracted and compared 68,097 Alu insertions in various primates looking for potential events of TE gene conversion and discovered 98 clear cases of Alu–Alu gene conversion, including 64 cases for which the direction of conversion was identified (e.g., AluS conversion to AluY). Gene conversion also does not necessarily affect the entire homologous sequence, and we detected 69 cases of partial gene conversion that resulted in virtual hybrids of two elements. Phylogenetic screening of gene-converted Alus revealed three clear hotspots of the process in the ancestors of Catarrhini, Hominoidea, and gibbons. In general, our systematic screening of orthologous primate loci for gene-converted TEs provides a new strategy and view of a post-integrative process that changes the identities of such elements.
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Liao, Pei-Qing, Yuh-Kun Chen, Helen Mae Mejia, Yuan-Yu Chien, Ya-Chien Lee, Choon-Meng Tan, Yi-Ching Chiu, and Jun-Yi Yang. "Detection, Identification, and Molecular Characterization of a 16SrII-V Subgroup Phytoplasma Associated with Nicotiana plumbaginifolia." Plant Disease 106, no. 3 (March 1, 2022): 805–9. http://dx.doi.org/10.1094/pdis-09-21-1968-sc.

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Nicotiana plumbaginifolia Viviani, commonly known as curl-leaved tobacco, is an annual herbaceous plant belonging to Solanaceae family. This plant is native to Mexico, South America, and parts of the Caribbean and has been reported to be present in Taiwan since 2006. In March 2021, N. plumbaginifolia Viviani, found in Yunlin County, Taiwan, was observed to have phyllody, virescence, and witches’-broom, which is consistent with the disease symptoms caused by phytoplasma infection. Samples of the healthy and symptomatic plants were collected for analysis of the causal agent associated with the diseased N. plumbaginifolia Viviani. Under transmission electron microscopy, the phytoplasma-like pleomorphic bodies were found in the sieve tubes of the diseased plants. The 16S ribosomal RNA (rRNA)-based phylogenetic analysis and the iPhyClassifier-based virtual restriction fragment length polymorphism study demonstrated that the phytoplasma identified in this study can be classified into the 16SrII-V subgroup, which is similar to the peanut witches’-broom phytoplasma, a ‘Candidatus phytoplasma aurantifolia’-related strain. Further identification of SAP54/PHYL1 and SAP11 homologs in the phytoplasma explain the disease symptoms of phyllody, virescence, and witches’-broom observed in diseased N. plumbaginifolia Viviani. The discovery of new phytoplasma plant hosts has gained scientific importance in light of the attempt to unravel an efficient strategy to fight the rapid spread of this disease, which poses a threat to the agricultural sector and food security in Taiwan.
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Debnath, Pradip, Bimal Debnath, Samhita Bhaumik, and Sudhan Debnath. "In Silico Identification of Potential Inhibitors of ADP‐Ribose Phosphatase of SARS‐CoV‐2 nsP3 by Combining E‐Pharmacophore‐ and Receptor‐Based Virtual Screening of Database." ChemistrySelect 5, no. 30 (August 11, 2020): 9388–98. http://dx.doi.org/10.1002/slct.202001419.

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Encinar, José Antonio, and Javier A. Menendez. "Potential Drugs Targeting Early Innate Immune Evasion of SARS-Coronavirus 2 via 2’-O-Methylation of Viral RNA." Viruses 12, no. 5 (May 10, 2020): 525. http://dx.doi.org/10.3390/v12050525.

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The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causing the COVID-19 respiratory disease pandemic utilizes unique 2′-O-methyltransferase (2′-O-MTase) capping machinery to camouflage its RNA from innate immune recognition. The nsp16 catalytic subunit of the 2′-O-MTase is unusual in its requirement for a stimulatory subunit (nsp10) to catalyze the ribose 2′-O-methylation of the viral RNA cap. Here we provide a computational basis for drug repositioning or de novo drug development based on three differential traits of the intermolecular interactions of the SARS-CoV-2-specific nsp16/nsp10 heterodimer, namely: (1) the S-adenosyl-l-methionine-binding pocket of nsp16, (2) the unique “activating surface” between nsp16 and nsp10, and (3) the RNA-binding groove of nsp16. We employed ≈9000 U.S. Food and Drug Administration (FDA)-approved investigational and experimental drugs from the DrugBank repository for docking virtual screening. After molecular dynamics calculations of the stability of the binding modes of high-scoring nsp16/nsp10–drug complexes, we considered their pharmacological overlapping with functional modules of the virus–host interactome that is relevant to the viral lifecycle, and to the clinical features of COVID-19. Some of the predicted drugs (e.g., tegobuvir, sonidegib, siramesine, antrafenine, bemcentinib, itacitinib, or phthalocyanine) might be suitable for repurposing to pharmacologically reactivate innate immune restriction and antagonism of SARS-CoV-2 RNAs lacking 2′-O-methylation.
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Valiunas, Deividas, Rasa Jomantiene, and Robert Edward Davis. "Evaluation of the DNA-dependent RNA polymerase β-subunit gene (rpoB) for phytoplasma classification and phylogeny." International Journal of Systematic and Evolutionary Microbiology 63, Pt_10 (October 1, 2013): 3904–14. http://dx.doi.org/10.1099/ijs.0.051912-0.

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Phytoplasmas are classified into 16Sr groups and subgroups and ‘Candidatus Phytoplasma ’ species, largely or entirely based on analysis of 16S rRNA gene sequences. Yet, distinctions among closely related ‘Ca. Phytoplasma ’ species and strains based on 16S rRNA genes alone have limitations imposed by the high degree of rRNA nucleotide sequence conservation across diverse phytoplasma lineages and by the presence in a phytoplasma genome of two, sometimes sequence-heterogeneous, copies of the 16S rRNA gene. Since the DNA-dependent RNA polymerase (DpRp) β-subunit gene (rpoB) exists as a single copy in the phytoplasma genome, we explored the use of rpoB for phytoplasma classification and phylogenetic analysis. We sequenced a clover phyllody (CPh) phytoplasma genetic locus containing ribosomal protein genes, a complete rpoB gene and a partial rpoC gene encoding the β′-subunit of DpRp. Primers and reaction conditions were designed for PCR-mediated amplification of rpoB gene fragments from diverse phytoplasmas. The rpoB gene sequences from phytoplasmas classified in groups 16SrI, 16SrII, 16SrIII, 16SrX and 16SrXII were subjected to sequence similarity and phylogenetic analyses. The rpoB gene sequences were more variable than 16S rRNA gene sequences, more clearly distinguishing among phytoplasma lineages. Phylogenetic trees based on 16S rRNA and rpoB gene sequences had similar topologies, and branch lengths in the rpoB tree facilitated distinctions among closely related phytoplasmas. Virtual RFLP analysis of rpoB gene sequences also improved distinctions among closely related lineages. The results indicate that the rpoB gene provides a useful additional marker for phytoplasma classification that should facilitate studies of disease aetiology and epidemiology.
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Kadi, Roqayah H., Khadijah A. Altammar, Mohamed M. Hassan, Abdullah F. Shater, Fayez M. Saleh, Hattan Gattan, Bassam M. Al-ahmadi, Qwait AlGabbani, and Zuhair M. Mohammedsaleh. "Potential Therapeutic Candidates against Chlamydia pneumonia Discovered and Developed In Silico Using Core Proteomics and Molecular Docking and Simulation-Based Approaches." International Journal of Environmental Research and Public Health 19, no. 12 (June 15, 2022): 7306. http://dx.doi.org/10.3390/ijerph19127306.

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Chlamydia pneumonia, a species of the family Chlamydiacea, is a leading cause of pneumonia. Failure to eradicate C. pneumoniae can lead to chronic infection, which is why it is also considered responsible for chronic inflammatory disorders such as asthma, arthritis, etc. There is an urgent need to tackle the major concerns arising due to persistent infections caused by C. pneumoniae as no FDA-approved drug is available against this chronic infection. In the present study, an approach named subtractive proteomics was employed to the core proteomes of five strains of C. pneumonia using various bioinformatic tools, servers, and software. However, 958 non-redundant proteins were predicted from the 4754 core proteins of the core proteome. BLASTp was used to analyze the non-redundant genes against the proteome of humans, and the number of potential genes was reduced to 681. Furthermore, based on subcellular localization prediction, 313 proteins with cytoplasmic localization were selected for metabolic pathway analysis. Upon subsequent analysis, only three cytoplasmic proteins, namely 30S ribosomal protein S4, 4-hydroxybenzoate decarboxylase subunit C, and oligopeptide binding protein, were identified, which have the potential to be novel drug target candidates. The Swiss Model server was used to predict the target proteins’ three-dimensional (3D) structure. The molecular docking technique was employed using MOE software for the virtual screening of a library of 15,000 phytochemicals against the interacting residues of the target proteins. Molecular docking experiments were also evaluated using molecular dynamics simulations and the widely used MM-GBSA and MM-PBSA binding free energy techniques. The findings revealed a promising candidate as a novel target against C. pneumonia infections.
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Manzoor, Ammara, Saira Amir, Farzana Gul, Muhammad Abubakar Sidique, Masood ur Rehman Kayani, Syed Shujaat Ali Zaidi, Sundus Javed, Syed Tahir Abbas Shah, and Arshan Nasir. "Characterization of the Gastrointestinal and Reproductive Tract Microbiota in Fertile and Infertile Pakistani Couples." Biology 11, no. 1 (December 28, 2021): 40. http://dx.doi.org/10.3390/biology11010040.

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The human microbiota is recognized as a vital “virtual” organ of the human body that influences human health, metabolism, and physiology. While the microbiomes of the gut, oral cavity, and skin have been extensively studied in the literature, relatively little work has been done on characterizing the microbiota of the human reproductive tract organs, and specifically on investigating its association to fertility. Here, we implemented a 16S ribosomal RNA (rRNA) amplicon sequencing approach to sequence and characterize the gut and genital tract microbiomes from several married Pakistani couples. The recruited individuals included 31 fertile and 35 infertile individuals, with ages ranging from 19–45 years. We identified several fluctuations in the diversity and composition of the gut and genital microbiota among fertile and infertile samples. For example, measures of α-diversity varied significantly between the genital samples donated by fertile and infertile men and there was overall greater between-sample variability in genital samples regardless of gender. In terms of taxonomic composition, Actinobacteria, Bacteroidetes, and Firmicutes fluctuated significantly between the gut microbiomes of fertile and infertile samples. Finally, biomarker analyses identified features (genera and molecular functions and pathways) that differed significantly between the fertile and infertile samples and in the past have been associated with bacterial vaginosis. However, we emphasize that 16S amplicon data alone has no bearing on individual health and is merely representative of microbial taxonomic differences that could also arise due to multiple other factors. Our findings, however, represent the first effort to characterize the microbiome associated with fertile and infertile couples in Pakistan and will hopefully pave the way for more comprehensive and broad-scale investigations in the future.
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45

Yang, Zhi-Hui, Ji-Xiang Huang, and Yi-Jian Yao. "Autoscreening of Restriction Endonucleases for PCR-Restriction Fragment Length Polymorphism Identification of Fungal Species, with Pleurotus spp. as an Example." Applied and Environmental Microbiology 73, no. 24 (October 26, 2007): 7947–58. http://dx.doi.org/10.1128/aem.00842-07.

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ABSTRACT A molecular method based on PCR-restriction fragment length polymorphism (RFLP) analysis of internal transcribed spacer (ITS) ribosomal DNA sequences was designed to rapidly identify fungal species, with members of the genus Pleurotus as an example. Based on the results of phylogenetic analysis of ITS sequences from Pleurotus, a PCR-RFLP endonuclease autoscreening (PRE Auto) program was developed to screen restriction endonucleases for discriminating multiple sequences from different species. The PRE Auto program analyzes the endonuclease recognition sites and calculates the sizes of the fragments in the sequences that are imported into the program in groups according to species recognition. Every restriction endonuclease is scored through the calculation of the average coefficient for the sequence groups and the average coefficient for the sequences within a group, and then virtual electrophoresis maps for the selected restriction enzymes, based on the results of the scoring system, are displayed for the rapid determination of the candidate endonucleases. A total of 85 haplotypes representing 151 ITS sequences were used for the analysis, and 2,992 restriction endonucleases were screened to find the candidates for the identification of species. This method was verified by an experiment with 28 samples representing 12 species of Pleurotus. The results of the digestion by the restriction enzymes showed the same patterns of DNA fragments anticipated by the PRE Auto program, apart from those for four misidentified samples. ITS sequences from 14 samples (of which nine sequences were obtained in this study), including four originally misidentified samples, confirmed the species identities revealed by the PCR-RFLP analysis. The method developed here can be used for the identification of species of other living microorganisms.
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46

Koendjbiharie, Jeroen G., Shuen Hon, Martin Pabst, Robert Hooftman, David M. Stevenson, Jingxuan Cui, Daniel Amador-Noguez, Lee R. Lynd, Daniel G. Olson, and Richard van Kranenburg. "The pentose phosphate pathway of cellulolytic clostridia relies on 6-phosphofructokinase instead of transaldolase." Journal of Biological Chemistry 295, no. 7 (December 22, 2019): 1867–78. http://dx.doi.org/10.1074/jbc.ra119.011239.

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The genomes of most cellulolytic clostridia do not contain genes annotated as transaldolase. Therefore, for assimilating pentose sugars or for generating C5 precursors (such as ribose) during growth on other (non-C5) substrates, they must possess a pathway that connects pentose metabolism with the rest of metabolism. Here we provide evidence that for this connection cellulolytic clostridia rely on the sedoheptulose 1,7-bisphosphate (SBP) pathway, using pyrophosphate-dependent phosphofructokinase (PPi-PFK) instead of transaldolase. In this reversible pathway, PFK converts sedoheptulose 7-phosphate (S7P) to SBP, after which fructose-bisphosphate aldolase cleaves SBP into dihydroxyacetone phosphate and erythrose 4-phosphate. We show that PPi-PFKs of Clostridium thermosuccinogenes and Clostridium thermocellum indeed can convert S7P to SBP, and have similar affinities for S7P and the canonical substrate fructose 6-phosphate (F6P). By contrast, (ATP-dependent) PfkA of Escherichia coli, which does rely on transaldolase, had a very poor affinity for S7P. This indicates that the PPi-PFK of cellulolytic clostridia has evolved the use of S7P. We further show that C. thermosuccinogenes contains a significant SBP pool, an unusual metabolite that is elevated during growth on xylose, demonstrating its relevance for pentose assimilation. Last, we demonstrate that a second PFK of C. thermosuccinogenes that operates with ATP and GTP exhibits unusual kinetics toward F6P, as it appears to have an extremely high degree of cooperative binding, resulting in a virtual on/off switch for substrate concentrations near its K½ value. In summary, our results confirm the existence of an SBP pathway for pentose assimilation in cellulolytic clostridia.
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47

Wei, Wei, Valeria Trivellone, Christopher H. Dietrich, Yan Zhao, Kristi D. Bottner-Parker, and Algirdas Ivanauskas. "Identification of Phytoplasmas Representing Multiple New Genetic Lineages from Phloem-Feeding Leafhoppers Highlights the Diversity of Phytoplasmas and Their Potential Vectors." Pathogens 10, no. 3 (March 16, 2021): 352. http://dx.doi.org/10.3390/pathogens10030352.

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Phytoplasmas are obligate transkingdom bacterial parasites that infect a variety of plant species and replicate in phloem-feeding insects in the order Hemiptera, mainly leafhoppers (Cicadellidae). The insect capacity in acquisition, transmission, survival, and host range directly determines the epidemiology of phytoplasmas. However, due to the difficulty of insect sampling and the lack of follow-up transmission trials, the confirmed phytoplasma insect hosts are still limited compared with the identified plant hosts. Recently, quantitative polymerase chain reaction (qPCR)-based quick screening of 227 leafhoppers collected in natural habitats unveiled the presence of previously unknown phytoplasmas in six samples. In the present study, 76 leafhoppers, including the six prescreened positive samples, were further examined to identify and characterize the phytoplasma strains by semi-nested PCR. A total of ten phytoplasma strains were identified in leafhoppers from four countries including South Africa, Kyrgyzstan, Australia, and China. Based on virtual restriction fragment length polymorphism (RFLP) analysis, these ten phytoplasma strains were classified into four distinct ribosomal (16Sr) groups (16SrI, 16SrIII, 16SrXIV, and 16SrXV), representing five new subgroups (16SrI-AO, 16SrXIV-D, 16SrXIV-E, 16SrXIV-F, and 16SrXV-C). The results strongly suggest that the newly identified phytoplasma strains not only represent new genetic subgroup lineages, but also extend previously undiscovered geographical distributions. In addition, ten phytoplasma-harboring leafhoppers belonged to seven known leafhopper species, none of which were previously reported insect vectors of phytoplasmas. The findings from this study provide fresh insight into genetic diversity, geographical distribution, and insect host range of phytoplasmas. Further transmission trials and screening of new potential host plants and weed reservoirs in areas adjacent to collection sites of phytoplasma harboring leafhoppers will contribute to a better understanding of phytoplasma transmission and epidemiology.
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48

Aftab, Fareesa, Alice Rodriguez-Fuguet, Luis Silva, Ikei S. Kobayashi, Jiao Sun, Katerina Politi, Elena Levantini, Wei Zhang, Susumu S. Kobayashi, and Wen Cai Zhang. "Abstract 451: AICAR targets oncogenic signaling pathways of MUC1-CT." Cancer Research 83, no. 7_Supplement (April 4, 2023): 451. http://dx.doi.org/10.1158/1538-7445.am2023-451.

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Abstract Lung cancer cells overexpress oncogenic mucin 1 (MUC1), whose C-terminal active subunit (MUC1-CT) is involved in lung tumor formation. Although a specific peptide against MUC1-CT has effectively blocked the MUC1 signaling pathway, intrinsic metabolites targeting MUC1 were not well studied. 5-aminoimidazole-4-carboxamide riboside (AICAR) is a purine biosynthesis intermediate and an analog of adenosine. Our study showed that high AICAR reduced lung tumor cell growth by increasing DNA damage and cell apoptosis. MUC1 was validated as one of the leading AICAR-binding proteins by virtual target screening and thermal stability assay. AICAR treatment dramatically degraded MUC1-CT at protein levels. Whole transcriptome analysis demonstrated that AICAR negatively regulated the Janus kinase (JAK) signaling pathway. Duolink proximity ligation assay revealed that JAK1 interacted with MUC1 directly, and AICAR treatment impaired this protein-protein interaction. Increased epidermal growth factor receptor (EGFR) activity was linked to upregulated expression of MUC1-CT in tissues from an EGFR transgenic mouse lung cancer model. AICAR treatment reduced phosphorylated EGFR, JAK1, and MUC1-CT in lung cancer cells. A mono-treatment with AICAR reduced tumor formation in a mouse lung xenograft model. Combination therapy with AICAR and small-molecule inhibitors against JAK1 or mutant EGFR reduced the growth of lung tissue-derived tumor organoids. Thus, our study has first disclosed a new ligand repressing the MUC1 activity in lung cancer that disrupts protein-protein interactions between MUC1-CT and other oncogenic proteins. Citation Format: Fareesa Aftab, Alice Rodriguez-Fuguet, Luis Silva, Ikei S. Kobayashi, Jiao Sun, Katerina Politi, Elena Levantini, Wei Zhang, Susumu S. Kobayashi, Wen Cai Zhang. AICAR targets oncogenic signaling pathways of MUC1-CT [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 451.
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49

Almeida, Karen H., Lisbeth Avalos-Irving, Steven Berardinelli, Kristen Chauvin, and Silvia Yanez. "Novel carbon skeletons activate human NicotinAMide Phosphoribosyl Transferase (NAMPT) enzyme in biochemical assay." PLOS ONE 18, no. 3 (March 30, 2023): e0283428. http://dx.doi.org/10.1371/journal.pone.0283428.

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Nicotinamide adenine dinucleotide (NAD) is a central molecule in cellular metabolism that has been implicated in human health, the aging process, and an array of human diseases. NAD is well known as an electron storage molecule, cycling between NAD and the reduced NADH. In addition, NAD is cleaved into nicotinamide and Adenine diphosphate ribose by NAD-consuming enzymes such as sirtuins, PARPs and CD38. There are numerous pathways for the biosynthesis of NAD to maintain a baseline concentration and thus avoid cellular death. The NAD salvage pathway, a two-step process to regenerate NAD after cleavage, is the predominant pathway for humans. Nicotinamide PhosphribosylTransferase (NAMPT) is the rate-limiting enzyme within the salvage path. Exposure to pharmacological modulators of NAMPT has been reported to either deplete or increase NAD levels. This study used a curated set of virtual compounds coupled with biochemical assays to identify novel activators of NAMPT. Autodock Vina generated a ranking of the National Cancer Institute’s Diversity Set III molecular library. The library contains a set of organic molecules with diverse functional groups and carbon skeletons that can be used to identify lead compounds. The target NAMPT surface encompassed a novel binding location that included the NAMPT dimerization plane, the openings to the two active site channels, and a portion of the known binding location for NAMPT substrate and product. Ranked molecules were evaluated in a biochemical assay using purified recombinant NAMPT enzyme. Two novel carbon skeletons were confirmed to stimulate NAMPT activity. Compound 20 (NSC9037) is a polyphenolic xanthene derivative in the fluorescein family, while compound 2 (NSC19803) is the polyphenolic myricitrin nature product. Micromolar quantities of compound 20 or compound 2 can double NAMPT’s product formation. In addition, natural products that contain high concentrations of polyphenolic flavonoids, similar to myricitrin, also stimulate NAMPT activity. Confirmation of a novel binding site for these compounds will further our understanding of the cellular mechanism leading to NAD homeostasis and better human health outcomes.
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50

Dutly, Fabrizio, and Martin Altwegg. "Whipple's Disease and “Tropheryma whippelii”." Clinical Microbiology Reviews 14, no. 3 (July 1, 2001): 561–83. http://dx.doi.org/10.1128/cmr.14.3.561-583.2001.

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SUMMARY Whipple's disease is a rare bacterial infection that may involve any organ system in the body. It occurs primarily in Caucasian males older than 40 years. The gastrointestinal tract is the most frequently involved organ, with manifestations such as abdominal pain, malabsorption syndrome with diarrhea, and weight loss. Other signs include low-grade fever, lymphadenopathy, skin hyperpigmentation, endocarditis, pleuritis, seronegative arthritis, uveitis, spondylodiscitis, and neurological manifestations, and these signs may occur in the absence of gastrointestinal manifestations. Due to the wide variability of manifestations, clinical diagnosis is very difficult and is often made only years or even decades after the initial symptoms have appeared. Trimethoprim-sulfamethoxazole for at least 1 year is usually considered adequate to eradicate the infection. The microbiological diagnosis of this insidious disease is rendered difficult by the virtual lack of culture and serodiagnostic methods. It is usually based on the demonstration of periodic acid-Schiff-positive particles in infected tissues and/or the presence of bacteria with an unusual trilaminar cell wall ultrastructure by electron microscopy. Recently, the Whipple bacteria have been characterized at the molecular level by amplification of their 16S rRNA gene(s). Phylogenetic analysis of these sequences revealed a new bacterial species related to the actinomycete branch which was named “Tropheryma whippelli.” Based on its unique 16S ribosomal DNA (rDNA) sequence, species-specific primers were selected for the detection of the organism in clinical specimens by PCR. This technique is currently used as one of the standard methods for establishing the diagnosis of Whipple's disease. Specific and broad-spectrum PCR amplifications mainly but not exclusively from extraintestinal specimens have significantly improved diagnosis, being more sensitive than histopathologic analysis. However, “T. whippelii” DNA has also been found in persons without clinical and histological evidence of Whipple's disease. It is unclear whether these patients are true asymptomatic carriers or whether differences in virulence exist among strains of “T. whippelii” that might account for the variable clinical manifestations. So far, six different “T. whippelii” subtypes have been found by analysis of their 16S-23S rDNA spacer region. Further studies of the pathogen “T. whippelii” as well as the host immune response are needed to fully understand this fascinating disease. The recent cultivation of the organisms is a promising major step in this direction.
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